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Novel Chelating Agents for Zirconium-89-Positron Emission Tomography (PET) Imaging: Synthesis, DFT Calculation, Radiolabeling, and In Vitro and In Vivo Complex Stability.

ABSTRACT: We report the synthesis and evaluation of novel chelating agents for zirconium-89 (⁸⁹Zr) with positron emission tomography (PET) imaging applications. New chelating agents NODHA, NOTHA, and NODHA-PY were constructed on 1,4,7-triazacyclononane (TACN) and possess hydroxamic acid or a pyridine ring as an acyclic binding moiety. The new chelating agents were theoretically studied for complexation with Zr(IV). Structures of Zr(IV)-NODHA, Zr(IV)-NOTHA, and Zr(IV)-NODHA-PY were predicted using density functional methods. NODHA was found to form stronger bonds with Zr(IV) when compared to NOTHA and NODHA-PY. The new chelating agents were evaluated for radiolabeling efficiency in binding ⁸⁹Zr. The corresponding [⁸⁹Zr]Zr-labeled chelators were evaluated for complex stability in human serum. All new chelating agents rapidly bound to ⁸⁹Zr in excellent radiolabeling efficiency at room temperature. Among the new [⁸⁹Zr]Zr-labeled chelators evaluated, [⁸⁹Zr]Zr-NODHA showed the highest stability in human serum without losing ⁸⁹Zr, and [⁸⁹Zr]Zr-NODHA-PY released a considerable amount of ⁸⁹Zr in human serum. [⁸⁹Zr]Zr-NODHA, [⁸⁹Zr]Zr-NODHA-PY, and [⁸⁹Zr]Zr-DFO were comparatively evaluated for in vivo complex stability by performing biodistribution studies using normal mice. [⁸⁹Zr]Zr-DFO had the lowest bone uptake at all time points, while [⁸⁹Zr]Zr-NODHA-PY showed poor stability in mice as evidenced by high bone accumulation at the 24 h time point. [⁸⁹Zr]Zr-NODHA exhibited better renal clearance but higher bone uptake than [⁸⁹Zr]Zr-DFO.

SUBMITTER: Kang CS

PROVIDER: S-EPMC9607665 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Novel Chelating Agents for Zirconium-89-Positron Emission Tomography (PET) Imaging: Synthesis, DFT Calculation, Radiolabeling, and In Vitro and In Vivo Complex Stability.

Kang Chi Soo CS Zhang Shuyuan S Wang Haixing H Liu Yujie Y Ren Siyuan S Chen Yanda Y Li Jingbai J Bandara Nilantha N Rogachev Andrey Yu AY Rogers Buck E BE Chong Hyun-Soon HS

ACS omega 20221013 42

We report the synthesis and evaluation of novel chelating agents for zirconium-89 (89Zr) with positron emission tomography (PET) imaging applications. New chelating agents NODHA, NOTHA, and NODHA-PY were constructed on 1,4,7-triazacyclononane (TACN) and possess hydroxamic acid or a pyridine ring as an acyclic binding moiety. The new chelating agents were theoretically studied for complexation with Zr(IV). Structures of Zr(IV)-NODHA, Zr(IV)-NOTHA, and Zr(IV)-NODHA-PY were predicted usi ...[more]

PMID: 36312419

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Project description:Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with (89)Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with (89)Zr-immuno-PET two requirements should be met for each (89)Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the (89)Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of (89)Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of (89)Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of (89)Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that (89)Zr-immuno-PET reflects specific, antigen-mediated binding. (89)Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop (89)Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.

Dataset Information

Novel Chelating Agents for Zirconium-89-Positron Emission Tomography (PET) Imaging: Synthesis, DFT Calculation, Radiolabeling, and In Vitro and In Vivo Complex Stability.

Publications

Novel Chelating Agents for Zirconium-89-Positron Emission Tomography (PET) Imaging: Synthesis, DFT Calculation, Radiolabeling, and <i>In Vitro</i> and <i>In Vivo</i> Complex Stability.

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